Departments of Urology, Pathology and the Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, 14642, USA; Department of Urology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430030, China.
Department of Urology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430030, China.
Cancer Lett. 2022 Jan 1;524:15-28. doi: 10.1016/j.canlet.2021.08.028. Epub 2021 Aug 27.
Sunitinib is the first-line drug for treating renal cell carcinoma (RCC), and it functions mainly through inhibition of tumor angiogenesis. However, the patients may become insensitive or develop resistance toward sunitinib treatment, but the underlying mechanisms have not yet been fully elucidated. Herein, it was found that sunitinib could have adverse effects of promoting RCC progression by increasing vascular mimicry (VM) formation of RCC cells. Mechanism dissection revealed that sunitinib can increase the expression of a long non-coding RNA (lncRNA), lncRNA-ECVSR, thereby enhancing the stability of estrogen receptor β (ERβ) mRNA. Subsequently, the increased ERβ expression can then function via transcriptional up-regulation of Hif2-α. Notably, sunitinib-increased lncRNA-ECVSR/ERβ/Hif2-α signaling resulted in an increased cancer stem cell (CSC) phenotype, thereby promoting VM formation. Furthermore, the sunitinib/lncRNA-ECVSR-increased ERβ expression can transcriptionally regulate lncRNA-ECVSR expression via a positive-feedback loop. Supportively, preclinical studies using RCC mouse xenografts demonstrated that combining sunitinib with the small molecule anti-estrogen PHTPP can increase sunitinib efficacy with reduced VM formation. Collectively, the findings of this study may aid in the development of potential biomarker(s) and novel therapies to better monitor and suppress RCC progression.
舒尼替尼是治疗肾细胞癌（RCC）的一线药物，主要通过抑制肿瘤血管生成起作用。然而，患者可能对舒尼替尼治疗产生不敏感或耐药，但潜在机制尚未完全阐明。本研究发现，舒尼替尼可能通过增加肾癌细胞的血管拟态（VM）形成而产生促进 RCC 进展的不良作用。机制剖析显示，舒尼替尼可增加长链非编码 RNA（lncRNA）lncRNA-ECVSR 的表达，从而增强雌激素受体β（ERβ）mRNA 的稳定性。随后，增加的 ERβ表达可以通过转录上调 Hif2-α发挥作用。值得注意的是，舒尼替尼增加的 lncRNA-ECVSR/ERβ/Hif2-α信号导致癌症干细胞（CSC）表型增加，从而促进 VM 形成。此外，舒尼替尼/lncRNA-ECVSR 增加的 ERβ表达可通过正反馈环转录调控 lncRNA-ECVSR 的表达。支持性的临床前研究使用肾细胞癌小鼠异种移植模型表明，联合使用舒尼替尼和小分子抗雌激素 PHTPP 可以提高舒尼替尼的疗效，同时减少 VM 形成。综上所述，本研究结果可能有助于开发潜在的生物标志物和新的治疗方法，以更好地监测和抑制 RCC 进展。
